1. Field of the Invention
The present invention relates generally to helix mimetics, as well as to compositions and methods related thereto, including chemical libraries of helix mimetics.
2. Description of the Related Art
Proteins are polymers of amino acids in which the carbon atoms and amide groups alternate to form a linear polypeptide, with the amino acid side chains projecting from the α-carbon atom of each amino acid. The sequence of amino acids and location of disulfide bridges (if any) are considered the “primary” protein structure. The “secondary” structure of a protein refers to the steric relationship of amino acid residues that are in close proximity to one another in the linear sequence. Such steric relationships give rise to periodic structure, including the helix. Helices comprise one of three classes of protein secondary structure and display amino acid side chains in a fixed spatial relationship to each other.
The helix is a rod-like structure wherein the polypeptide chain forms the inner part of the rod, and the side chains extend outward in a helical array. The helix is stabilized by hydrogen bonds between the NH and CO groups of the polypeptide chain. The two most common helices, 310- and alpha-helices, are found in nature. The latter being the most abundant secondary structure in proteins. More specifically, for 310-helix, the hydrogen of the NH group of each amino acid (i.e., amino acid residue “n”) is hydrogen bonded to the oxygen of the CO group that is located three amino acid residues behind in the linear polypeptide (i.e., amino acid residue “n-3”). Such hydrogen bonding is illustrated below: While only a single hydrogen bond is depicted above for purpose of illustration, each of the CO and NH groups of the linear polypeptide are hydrogen bonded in the 310-helix. In particular, each amino acid is related to the next by a translation of 2.0 Å along the helix axis and a rotation of 120°, which gives 3 amino acid residues per turn of the 310-helix. The pitch of the 310-helix is 6.0 Å (the product of the translation, 2.0 Å, and the number of residues per turn, 3), and the radius of the 310-helix is 1.9 Å.
For alpha-helix, the most abundant secondary structure in proteins, the hydrogen of the NH group of each amino acid (i.e., amino acid residue “n”) is hydrogen bonded to the oxygen of the CO group that is located four amino acid residues behind in the linear polypeptide (i.e., amino acid residue “n-4”). Such hydrogen bonding is illustrated below: Again, while only a single hydrogen bond is depicted above for purpose of illustration, each of the CO and NH groups of the linear polypeptide are hydrogen bonded in the alpha-helix. In particular, each amino acid is related to the next by a translation of 1.5 Å along the helix axis and a rotation of 100°, which gives 3.6 amino acid residues per turn of the alpha-helix. The pitch of the alpha-helix is 5.4 Å (the product of the translation, 1.5 Å, and the number of residues per turn, 3.6), and the radius of the alpha-helix is 2.3 Å. The “screw sense” of the alpha-helix can be right-handed (clockwise) or left-handed (counter-clockwise). While a few left-handed alpha-helixes do exist, most alpha-helixes found in naturally occurring proteins are right-handed.
In the absence of interactions other than hydrogen-bonding, the alpha-helix is the preferred form of the polypeptide chain since, in this structure, all amino acids are in identical orientation and each forms the same hydrogen bonds. Thus, polyalanine (i.e., {—NHCH(CH3)CO—}r) exists as an alpha-helix. However, the presence of other amino acids within the polypeptide chain may cause instability to the alpha-helix. In other words, the amino acid side chains do not participate in forming the alpha-helix, and may hinder or even prevent alpha-helix formation. A striking example of such side chain dependency on alpha-helix formation is polylysine (i.e., {—NHCH((CH2)4NH2)CO—}n). At a pH below 10, the NH2 moiety in the side chain of lysine is charged (i.e., NH3+), and electrostatic repulsion totally destroys the alpha-helix structure. Conversely, at a pH above 10, the alpha-helix structure is preferred.
The helix constitutes one of the principle architectural features of peptides and proteins, and are important structural elements in a number of biological recognition events, including ligand-receptor interactions, protein-DNA interactions, protein-RNA interactions, and protein-membrane interactions. A number of alpha-helix mimetics have been developed to stabilize the alpha-helical structure of a natural or synthetic peptide or protein, particularly the secondary structure of helices. For example, U.S. Pat. Nos. 5,446,128, and 5,710,245 disclose compounds that initiate and stabilize the three-dimensional structure of the helix, while U.S. Pat. Nos. 5,840,833 and 5,859,184 disclose compounds with covalent bonds linking the inner core or backbone of the helix, and thus stabilize the three-dimensional structure of the helix.
In view of the important biological role played by the helix, there is a need in the art for compounds that can mimic the helix structure. There is also a need in the art for methods of making stable helix mimetics, as well as the use of such stabilized structures to effect or modify biological recognition events which involve helical structures. The present invention fulfills these needs and provides further related advantages.